A recurring problem in the treatment of patients, in particular children and the elderly, is their inability or unwillingness to swallow solid oral dosage forms such as tablets or capsules. The problem is, however, not uncommon in healthy adults as well. This problem is not trivial, the inability or unwillingness of some people to take solid oral dosage forms can severely compromise the patient's compliance with a prescribed treatment protocol. Moreover, due to embarrassment, many patients are unwilling to tell their doctor of their problem so that the doctor can consider other drugs and/or alternate dosage forms. Such a lack of compliance can compromise treatment or cure.
If an orally administered drug has such a taste that is acceptable to the patient and the pharmacokinetic characteristics allow reasonable administration regimens, such as once or twice daily, the drug might be formulated in a syrup, elixir, suspension or other liquid dosage forms. Unfortunately, in many cases the native taste of the drug is unpleasant and not amenable to taste-masking by the addition of sweeteners of flavours. Also, many drugs have such pharmacokinetic parameters that demand administration at short intervals, disrupting sleep and other activities. The taste and/or pharmacokinetic deficiencies can be corrected by the use of various coating and/or matrices and/or by modifying the crystalline structure, et cetera. U.S. Pat. No. 6,589,955 illustrates such an approach. The resulting material after micro-encapsulation or crystallization or other strategies might be a monolithical unit, one unit containing the whole dose, or multi-particles, each particle containing a fraction of the total dosage. The monolithical units are often unacceptable to people having the swallowing problems described above. The multi-particles must be further processed into finished dosage forms such as tablets and capsules with the same limitation as the monolithical units or other forms specifically designed for children and/or adults unable to swallow oral solid dosage forms. Finally, some substances are administered in such high doses that the resulting tablets or capsules are either very large or that many tablets or capsules must be administered simultaneously, in either case, causing discomfort. The multi-particles may be presented as a powder. This powder might then be formulated into tablets or capsules meant to be swallowed whole. Those tablets and capsules as such are inappropriate for patients with swallowing difficulties. Patients (or they providers in the case of children) are often instructed to open the capsules (or crush the tablets) and to sprinkle the powder on syrup or pudding or applesauce or similar and then administered. This approach has limitations. The carrier (syrup, pudding, applesauce) is not a well defined entity and different carriers might interact differently with the multi-particles and/or drug and thereby compromise the treatment. Also, children might object to the grittiness in the material. Syrups do not necessarily resemble types of food or beverages that children are used to consume.
Alternatively the powder can be formulated into effervescent granules or tablets. These granules or tablets are intended to be dissolved in an aqueous liquid requiring the provision of a glass of liquid and a waiting period sufficient to allow the tablet to completely dissolve and the resulting volume might be considerable. Often, these dosage forms leave an objectionable deposit in the glass, which may represent a non-ingested part of the drug. Effervescent formulations are, in general more appropriate for adults although some commercial vitamin preparations for children use this approach.
Another category is the fast-melting tablets meant to be put on the tongue and disintegrate upon contact with saliva. The might be effervescent or non-effervescent. Yet another solution is to dispense the multi-particles in lozenges, chewable tablets and chewing gum.
One example of these approaches was described in Wehling et al., U.S. Pat. No. 5,178,878, which relates to certain effervescent dosage forms including microparticles. The effervescent dosage forms of Wehling et al. provide a significant advance over the art in that they provide an effervescent dosage form for direct oral administration. The dosage form is designed to disintegrate rapidly in the mouth releasing its microparticles as a slurry for ingestion. The dosage forms produced in accordance with Wehling et al. can be placed in the patient's mouth and the effervescence contained therein will be activated by contact with the patient's saliva. The tablet will then disintegrate in a number of seconds. However, the effervescence on the tongue may be unpleasant to some adults and to many children.
Kallstrand, et al., U.S. Pat. No. 4,994,260 relates to a pharmaceutical mixture. The mixture is used for the controlled release of a substance. According to Kallstrand et al., a liquid dosage form is produced using either a dry powder or microcapsules, which are suspended in a solution of a release-controlling substance, also referred to as a “sink”. Alternatively, it is possible to encapsulate the release-controlling substance, together with a drug, within an encapsulating shell. The release-controlling substance may include, inter alia, carbohydrates and carbohydrate-related compounds, disaccharides, monosaccharides, glycerol, glycol, glycosides of monosaccharides and substances derived from ethyleneglycol.
Boder et al., U.S. Pat. No. 5,126,151 relates to an encapsulation mixture. Boder et al. refers to the construction of gums and candies in oral dosage forms. According to Boder et al., microcapsules are produced including a core material which can be selected from a wide variety of materials including sweeteners, medicaments, drugs, flavoring agents and the like. These materials can be used, either singularly or in combination, in either a single or multiple part delivery systems. That is, one or more of these materials may be present within one coating matrix or maybe separately coated by the matrix and employed alone or in combination in the final product. The resulting formulations are said to be able to provide a masking of unpleasant tasting drugs such as potassium chloride and the like, making consumption of the drug more appealing to the public. The dosage forms may be prepared in chewable tablet form.
Schobel et al., U.S. Pat. No. 4,824,681, and Wei et al., U.S. Pat. No. 4,590,075. Encapsulated sweeteners have also been used to provide an extended release of sweetening in, for example, chewing gum, see for example European patent application EPO 87-810747 to Schobel et al. and in bakery products such as disclosed in WO 91-US9434 filed Dec. 17, 1991 to Redding et al.
Further, in WO 01/76610 Simek et al describe a pharmaceutical composition containing calcium or mixture of calcium and vitamin D or mixture of calcium and magnesium and adjuvants, presented in the form of soluble powder, which by addition of liquids and mechanical mixing, forms a gelatinous suspension resembling a pudding.
U.S. Pat. No. 6,709,678 discloses an oral pharmaceutical composition to be dispersed in an aqueous carrier prior to administration comprising a multiplicity of particles consisting of a drug core individually coated with one or more layers with a hydratable polymer. The preferred hydratable polymers are preferably alginates, carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. The coating is applied by conventional coating methods with a powder mixture in a spheronizer or by spraying on a solution or suspension of the coating materials to the core. The aim of the hydrated formulation is to obtain a formulation in a single, slippery, non disintegrating mouldable coherent viscous plastic mass, which does not adhere to the mucosa.
WO2004/096906 A1 discloses a thickenable composition in water-containing liquid form which upon addition of further water increases in viscosity. The composition comprises different anionic polymers such as xanthan together with alginate, carboxymethyl cellulose, carrageenan, an acrylate polymer or pectin.
WO 2005/007074 A2 published on 27 Jan. 2005 discloses a gellan gum based oral controlled release dosage form for gastric retention. The formulation is swallowed in a non hydrated form such as a tablet and it is expected that the formulation when reaching the aqueous environment of the stomach would form a strong gel.
The present invention proposes an improvement over the art by providing a substantially water free dosage form, containing particulate material such as, e.g., particulate units, that is/are designed for the purpose of masking the taste of drug substance(s) and/or to provide controlled release of a drug substance or drug substances. In turn the particulate material may be coated and/or mixed with components that, upon exposure to water will swell into a soft pudding-like, mousse-like or soufflé-like semisolid mass that has a sensory-acceptable mouth-feel and taste as determined and judged by a professional taste panel. Further, the invention provides a vehicle to be combined prior to administration with particulate matter such as microencapsulated drugs.